The present invention relates to a novel pyrimidine derivative having an antitumor activity, a cytostatic activity, and an inhibitory activity against a signal derived from Ras oncogene products.
The oncogene xe2x80x9crasxe2x80x9d such as H-ras, K-ras, and N-ras is mutated and activated in many of neoplasms. The xe2x80x9cRasxe2x80x9d, the products of ras oncogene, strongly concerns tumorigenesis caused by acceleration of cell cycle and induction of expression of many of genes associated with a malignant conversion such as a vascular endothelial growth factor and type-IV coliagenase. Especially, it is found that there is highly frequent ras mutation in solid tumor such as pancreatic cancer ( greater than 80%), colon cancer ( greater than 40%), and lung cancer ( greater than 20%) which are difficult to be cured by using existing chemotherapeutics. Therefore, it is considered that Ras is one of the most important target molecules in the development of the chemotherapeutics against them.
A farnesyl-protein-transferase (FPT) inhibitor (FPTI) is known as chemotherapeutics of which target are Ras (WO95/13059, WO95/25086, WO95/25092, W095134535, U.S. Pat. No. 5,608,067, and JP-A-7-112930).
In the cells expressing activated Ras, the excess signals reach cell nucleus through some signaling pathways and some signal transmitter molecules such as MAPK (Mitogen Activated Protein Kinase) and P13K (Phosphatidylinositol-3-Kinase). The signals activate the transcription factors such as AP1 (Activator Protein-1) and ETS (E26 transformation specific) in the cell nucleus and then they induce the expression of many genes related to malignant features through transcription activation element such as Ras Responsive Element (RRE). Therefore, it is possible to repress the malignant conversion of the cancer cells, when the signal transmission (a signal derived from ras oncogene products) is inhibited.
In the above situation, the inventors of the present invention have studied on the antitumor agent having an inhibitory activity against a signal derived from Ras oncogene products.
The activation of gene expression through RRE is in proportion to a signal derived from Ras and the signal can be measured by the amount of its expression. The inventors of the present invention artificially made cells having activated Ras wherein expression of firefly luciferase gene, reporter gene, is regulated by RRE and carried out a screening of the inhibitors taking luciferase activity shown by the cells as an index of signals through Ras. As a result, the inventors of the present invention found that a series of pyrimidine derivatives have a strong inhibitory activity against a signal derived from Ras oncogene products.
The present invention relates to I) a compound represented by the formula (I): 
wherein R1, R2, R3, and R4 are each independently hydrogen atom, optionally substituted alky, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, an optionally substituted non-aromatic heterocyclic group, or acyl; or
R1 and R2, R3 and R4, and R2 and R3 each taken together with the adjacent nitrogen atom form the same or different 3- to 6-membered ring optionally containing O, S, or N, provided that R1 and R2 and R3 and R4 do not form a ring when R2 and R3 taken together form a ring;
R5 and R6 are each independently hydrogen atom, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkyloxy, alkylthio, optionally substituted alkyloxycarbonyl, optionally substituted aryl, optionally substituted heteroaryl, halogen, hydroxy, mercapto, optionally substituted amino, carboxy, cyano, or nitro;
X is xe2x80x94N(R7)xe2x80x94, xe2x80x94NHxe2x80x94NHxe2x80x94, xe2x80x94Oxe2x80x94, or xe2x80x94Sxe2x80x94 wherein R7 is hydrogen atom or optionally substituted alkyl;
Y is optionally substituted 5-membered non-aromatic heterocycle-diyl or optionally substituted 5-membered heteroaryl-diyl;
Z is optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aryl alkenyl, or optionally substituted alkenyl; the prodrugs thereof, or their pharmaceutically acceptable salts, or their solvates.
In more detail, the present invention relates to:
II) a compound represented by the formula (II): 
xe2x80x83wherein R8, R9, R10, and R11 are each independently hydrogen atom, optionally substituted alkyl, alkenyl, alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, a non-aromatic heterocyclic group, or acyl;
W is xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, or xe2x80x94N(RA)xe2x80x94 wherein RA is hydrogen atom or optionally substituted alkyl;
R5, R6, X, and Z are as defined above, the prodrugs thereof, or their pharmaceutically acceptable salts, or their solvates,
III) a compound represented by the formula (III): 
xe2x80x83wherein R5, R6, R8, R9, R10, R11, and Z are as defined above, the prodrugs thereof, or their pharmaceutically acceptable salts, or their solvates,
IV) a compound represented by the formula (IV): 
xe2x80x83wherein R12 is hydrogen atom or alkyl;
V is optionally substituted aryl;
R8, R9, R10, and R11 are as defined above, the prodrugs thereof, or their pharmaceutically acceptable salts, or their solvates,
V) a compound, the prodrugs thereof, or their pharmaceutically acceptable salts, or their solvates as described in above I), wherein R1, R2, R3, and R4 are each independently hydrogen atom, optionally substituted alkyl, alkenyl, alkynyl, or acyl,
VI) a compound, the prodrugs thereof, or their pharmaceutically acceptable salts, or their solvates as described in any one of the above II) to IV), wherein R8, R9, R10, and R11 are each independently hydrogen atom, optionally substituted alkyl, alkenyl, alkynyl, or acyl,
VII) a pharmaceutical composition which contains as active ingredient a compound as described in any one of I) to VI),
VIII) a pharmaceutical composition for use as an antitumor agent which contains as active ingredient a compound as described in any one of I) to VI)s,
IX) a pharmaceutical composition for use as a cytostatic agent which contains as described in any one of I) to VI),
X) a pharmaceutical composition for use as an inhibitor against a signal derived from Ras oncogene products which contains as active ingredient a compound as described in any one of I) to VI),
XI) use of a compound of any one of I) to VI) for the preparation of a pharmaceutical composition for treating cancer, and
XII) a method of treating a mammal, including a human, to alleviate the pathological effects of cancer; which comprises administration to the mammal of a compound as described in any one of I) to VI).
The term xe2x80x9calkylxe2x80x9d employed alone or in combination with other terms in the present specification includes a straight or branched chain monovalent hydrocarbon group having 1 to 8 carbon atoms. Examples of the alkyl include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl, n-heptyl, n-octyl and the like. Preferably, C1 to C6 alkyl is exemplified. More preferably, C1 to C3 alkyl is exemplified.
The term xe2x80x9calkenylxe2x80x9d employed alone or in combination with other terms in the present specification includes a straight or branched chain monovalent hydrocarbon group having 2 to 8 carbon atoms and one or more double bonds. An example of the alkenyl includes vinyl, allyl, propenyl, crotonyl, prenyl, a variety of butenyl isomers and the like. Preferably, C2 to C6 alkenyl is exemplified. More preferably, C2 to C3 alkenyl is exemplified.
The term xe2x80x9calkynylxe2x80x9d employed alone or in combination with other terms in the present specification includes a straight or branched chain monovalent hydrocarbon group having 2 to 8 carbon atoms and one or more triple bonds. The alkynyl may contain (a) double bond(s). An example of the alkenyl includes ethynyl, propynyl, 6-heptynyl, 7-octynyl, and the like. Preferably, C2 to C6 alkynyl is exemplified. More preferably, C2 to C3 alkynyl is exemplified.
The term xe2x80x9carylxe2x80x9d employed alone or in combination with other terms in the present specification includes a monocyclic or condensed cyclic aromatic hydrocarbon. An example of the aryl includes phenyl, 1-naphthyl, 2-naphthyl, anthryl and the like. Preferably, phenyl, 1-naphthyl, and 2-naphthyl are exemplified. More preferably, phenyl is exemplified.
The term xe2x80x9caralkylxe2x80x9d in the present specification includes a group wherein the above-mentioned xe2x80x9calkylxe2x80x9d is substituted with the above-mentioned xe2x80x9carylxe2x80x9d. An example of aralkyl includes benzyl, phenethyl (e.g., 2-phenylethyl), phenylpropyl (e.g., 3-phenylpropyl), naphthylmethyl (e.g., 1-naphthylmethyl and 2-naphthylmethyl), anthrylmethyl (e.g., 9-anthrylmethyl) and the like. Preferably, benzyl and phenylethyl are exemplified.
The term xe2x80x9cheteroarylxe2x80x9d employed alone or in combination with other terms in the present specification includes a 5- to 6-membered aromatic cyclic group which contains one or more hetero atoms selected from the group consisting of oxygen, sulfur, and nitrogen atoms in the ring and may be fused with the above mentioned xe2x80x9carylxe2x80x9d, xe2x80x9cheteroarylxe2x80x9d, xe2x80x9ccarbocyclic groupxe2x80x9d, and xe2x80x9cnon-aromatic heterocyclic groupxe2x80x9d. Heteroaryl is bonded at any possible position when the heteroaryl is a condensed ring. Examples of the heteroaryl are pyrrolyl (e.g., 1-pyrrolyl), indolyl (e.g., 3-indolyl), carbazolyl (e.g., 3-carbazolyl), imidazolyl (e.g., 4- imidazolyl), pyrazolyl (e.g., 3-pyrazolyl and 5-pyrazolyl), benzimidazolyl (e.g., 2-benzimidazolyl), indazolyl (e.g., 3-indazolyl), indolizinyl (e.g., 6-indolizinyl), pyridyl (e.g., 3-pyridyl and 4-pyridyl), quinolyl (e.g., 5-quinolyl), isoquinolyl (e.g., 3-isoquinolyl), acridinyl (e.g., 1-acridinyl), phenanthridinyl (e.g., 2-phenanthridinyl), pyridazinyl (e.g., 3-pyridazinyl), pyrimidinyl (e.g., 4-pyrimidinyl), pyrazinyl (e.g., 2-pyrazinyl), cinnolinyl (e.g., 3-cinnolinyl), phthalazinyl (e.g., 2-phthalazinyl), quinazolinyl (e.g., 2-quinazolinyl), isoxazolyl (e.g., 3-isoxazolyl), benzisoxazolyl (e.g., 3-benzisoxazolyl), oxazolyl (e.g., 2-oxazolyl), benzoxazolyl (e.g., 2-benzoxazolyl), benzoxadiazolyl (e.g., 4-benzoxadiazolyl), isothiazolyl (e.g., 3-isothiazolyl), benzisothiazolyl (e.g., 2-benzisothiazolyl), thiazolyl (e.g., 4-thiazolyl), benzothiazolyl (e.g., 2-benzothiazolyl), furyl (e.g., 2-furyl and 3-furyl), benzofuryl (e.g., 3-benzofuryl), thienyl (e.g., 2-thienyl and 3-thienyl), benzothienyl (e.g., 2-benzothienyl), tetrazolyl, oxadiazolyl (e.g., 1,3,4-oxadiazolyl and 1,2,4-oxadiazolyl), oxazolyl, thiadiazolyl (e.g., 1,3,4-thiadiazolyl and 1,2,4-thiadiazolyl), 4H-1,2,4-triazolyl, quinoxalinyl, 2-pyridone-3-yl, and the like. Preferably, pyridyl, pyrazinyl, furyl, thienyl and the like are exemplified.
The term xe2x80x9c5-membered heteroaryl-diylxe2x80x9d herein used includes a 5-membered divalent group derived from above-mentioned xe2x80x9cheteroarylxe2x80x9d. Examples of the 5-membered heteroaryl-diyl are 2,5-furandiyl, 2,5-thiophendiyl, 2,5-pyrroldiyl, 3,5-pyrazoldiyl, 2,5-(1,3,4-oxadiazole)diyl, 3,5-(1,2,4-oxadiazole)diyl, 2,5-oxazoldiyl, 3,5-isoxazoldiyl, 2,5-(1,3,4-thiadiazole)diyl, 3,5-(1,2,4-thiadiazole)diyl, 3,5-(4H-1,2,4-triazole)diyl, and the like.
The term xe2x80x9cnon-aromatic heterocyclic groupxe2x80x9d employed alone or in combination with other terms in the present specification includes a 5- to 7-membered non-aromatic heterocyclic group which contains one or more hetero atoms selected from the group consisting of oxygen, sulfur, and nitrogen atoms in the ring and a cyclic group wherein two or more of the above-mentioned heterocyclic groups are fused. Examples of the heterocyclic group are pyrrolidinyl (e.g., 1-pyrrolidinyl), pyrazolidinyl (e.g., 1-pyrazolidinyl), piperidinyl (e.g., piperidino and 2-piperidinyl), piperazinyl (e.g., 1-piperazinyl), morpholinyl (e.g., morpholino and 3-morpholinyl), and the like.
The term xe2x80x9c5-membered non-aromatic heterocycle-diylxe2x80x9d herein used includes a 5-membered divalent group derived from the above-mentioned xe2x80x9cnon-aromatic heterocyclic groupxe2x80x9d. Examples of the 5-membered non-aromatic heterocycle-diyl are pyrrolidindiyl (e.g., 2,5-pyrrolidindiyl) and the like.
The term xe2x80x9ccarbocyclic groupxe2x80x9d herein used includes a 3- to 7-membered non-aromatic carbocyclic group. Examples of the carbocyclic group are cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl), cycloalkenyl (e.g., cyclopentenyl and cyclohexenyl), and the like.
In this specification, examples of the ring represented by xe2x80x9cR1 and R2, R3 and R4, and R2 and R3 each taken together with the adjacent nitrogen atom form the same or different 3- to 6-membered non-aromatic heterocyclic ringxe2x80x9d are aziridine, pyrrolidine, piperidine, piperazine, morpholine, imidazolidine, pyrazolidine, pyrrole, py dine, triazine, and the like.
The term xe2x80x9cacylxe2x80x9d employed alone or in combination with other terms in the present specification includes alkylcarbonyl of which alkyl part is the above-mentioned xe2x80x9calkylxe2x80x9d and arylcarbonyl of which aryl part is the above-mentioned xe2x80x9carylxe2x80x9d. Examples of the acyl are acetyl, propanoyl, benzoyl, and the like.
The term xe2x80x9chalogenxe2x80x9d herein used means fluoro, chloro, bromo, and iodo.
Examples of xe2x80x9calkyloxyxe2x80x9d herein used are methyloxy, ethyloxy, n-propyloxy, isopropyloxy, n-butyloxy, isobutyloxy, sec-butyloxy, tert-butyloxy, and the like. Preferably, methyloxy, ethyloxy, n-propyloxy, and isopropyloxy are exemplified.
Examples of xe2x80x9calkylthioxe2x80x9d herein used are methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutylthio, sec-butylthio, tert-butylthio, and the like. Preferably, methylthio, ethylthio, n-propylthio, and isopropylthio are exemplified.
Examples of xe2x80x9calkyloxycarbonylxe2x80x9d herein used are methyloxycarbonyl, ethyloxycarbonyl, n-propyloxycarbonyl, and the like.
The term xe2x80x9coptionally substituted aminoxe2x80x9d herein used means amino substituted with one or two of the above-mentioned xe2x80x9calkylxe2x80x9d, xe2x80x9caralkylxe2x80x9d, xe2x80x9cacylxe2x80x9d, optionally substituted sulfonyl (e.g., alkyloxyphenylsulfonyl), arylalkylene (e.g., benzylidene), alkylsulfonyl, carbamoyl and the like or non-substituted amino. Examples of the optionally substituted amino are amino, methylamino, ethylamino, dimethylamino, ethylmethylamino, diethylamino, benzylamino, benzoylamino, acetylamino, propionylamino, tert-butyloxycarbonylamino, benzylidenamino, methylsulfonylamino, 4-methoxyphenylsulfonylamino, and the like. Preferably, amino, methylamino, dimethylamino, diethylamino, acetylamino are exemplified.
Substituentson the aromatic ring of xe2x80x9coptionally substituted aralkylxe2x80x9d are, for example, hydroxy, alkyloxy (e.g., methyloxy and ethyloxy), mercapto, alkylthio (e.g., methylthio), cycloalkyl (e.g., cyclopropyl, cyclobutyl, and cyclopentyl), halogen (e.g., fluoro, chloro, bromo, and iodo), carboxy, alkyloxycarbonyl (e.g., methyloxycarbonyl and ethyloxycarbonyl), nitro, cyano, haloalkyl (e.g., trifluoromethyl), aryloxy (e.g., phenyloxy), optionally substituted amino (e.g., amino, methylamino, dimethylamino, diethylamino, and benzylidenamino), alkyl (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, and neopentyl), alkenyl (e.g., vinyl and propenyl), alkynyl (e.g., ethynyl and phenylethynyl), formyl, lower alkanoyl (e.g., acetyl and propionyl), acyloxy (e.g., acetyloxy), acylamino, alkylsulfonyl (e.g., methylsulfonyl), and the like. These substituents may be substituted at one or more possible position(s).
Substituents of xe2x80x9coptionally substituted alkylxe2x80x9d, xe2x80x9coptionally substituted alkyloxyxe2x80x9d, and xe2x80x9coptionally substituted alkyloxycarbonylxe2x80x9d are, for example, hydroxy, alkyloxy (e.g., methyloxy and ethyloxy), mercapto, alkylthio (e.g., methylthio), cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl), halogen (e.g., fluoro, chloro, bromo, and iodo), carboxy, alkyloxycarbonyl (e.g., methyloxycarbonyl and ethyloxycarbonyl), nitro, cyano, haloalkyl (e.g., trifluoromethyl), optionally substituted amino (e.g., amino, methylamino, dimethylamino, carbamoylamino, and tert-butyloxycarbonylamino), acyloxy (e.g., acetyloxy), optionally substituted aralkyloxy (e.g., benzyloxy and 4-methyloxyphenylmethyloxy), and the like. These substituents may be substituted at one or more possible position(s).
Substituents of xe2x80x9coptionally substituted alkenylxe2x80x9d and xe2x80x9coptionally substituted alkynylxe2x80x9d are, for example, hydroxy, alkyloxy (e.g., methyloxy and ethyloxy), mercapto, alkylthio (e.g., methylthio), cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl), halogen (e.g., fluoro, chloro, bromo, and iodo), carboxy, alkyloxycarbonyl (e.g., methyloxycarbonyl and ethyloxycarbonyl), nitro, cyano, haloalkyl (e.g., trifluoromethyl), optionally substituted amino (e.g., amino, methylamino, dimethylamino, carbamoylamino, and tert-butyloxycarbonylamino), acyloxy (e.g., acetyloxy), optionally substituted aralkyloxy (e.g., benzyloxy and 4-methyloxyphenylmethyloxy), optionally substituted aryl (e.g., phenyl), and the like. These substituents may be substituted at one or more possible position(s).
The preferable examples of xe2x80x9coptionally substituted alkylxe2x80x9d are methyl, ethyl, n-propyl, isopropyl, n-butyl, trifluoromethyl, 2,2,2-trifluoroethyl, hydroxymethyl, cyclohexylmethyl, carboxyethyl, acetyloxyethyl, and benzyloxymethyl. More preferably, methyl, ethyl, n-propyl, isopropyl, n-butyl, trifluoromethyl, 2,2,2-trifluoroethyl are exemplified.
Substituents of xe2x80x9coptionally substituted arylxe2x80x9d, xe2x80x9coptionally substituted heteroarylxe2x80x9d, xe2x80x9coptionally substituted 5-membered heteroaryl-diylxe2x80x9d, xe2x80x9coptionally substituted 5-membered non-aromatic heterocycle-diylxe2x80x9d, and xe2x80x9can optionally substituted non-aromatic heterocyclic groupxe2x80x9d are, for example, hydroxy, optionally substituted alkyloxy (e.g., methyloxy, ethyloxy, n-propyloxy, isopropyloxy, ethyloxycarbonylmethyloxy, carboxymethyloxy and 4-methoxyphenylmethyloxy), mercapto, alkylthio (e.g., methylthio), cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl), halogen (e.g., fluoro, chloro, bromo, and iodo), carboxy, alkyloxycarbonyl (e.g., methyloxycarbonyl, ethyloxycarbonyl, and tert-butyloxycarbonyl), nitro, cyano, haloalkyl (e.g., trifluoromethyl), aryloxy (e.g., phenyloxy), optionally substituted amino (e.g., amino, methylamino, dimethylamino, ethylamino, diethylamino, N,N-acetylmethylamino, benzylidenamino, 4-methoxyphenylsulfonylamino, methylsulfonylamino, benzoylamino, acetylamino, propionylarmino, and tert-butyloxycarbonylamino), optionally substituted aminosulfonyl (e.g., aminosulfonyl), optionally substituted alkyl (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, t-butyloxycarbonylaminomethyl, and aminomethyl), alkenyl (e.g., vinyl, propenyl, and prenyl), optionally substituted alkynyl (e.g., ethynyl and phenylethynyl), alkenyloxy (e.g., propenyloxy and prenyloxy), formyl, acyl (e.g., acetyl, propionyl, and benzoyl), acyloxy (e.g., acetyloxy), optionally substituted carbamoyl (e.g., carbamoyl and dimethylaminocarbonyl), alkylsulfonyl (e.g., methylsulfonyl), aryl (e.g., phenyl), aralkyl (e.g., benzyl), carbothioamide, optionally substituted heterocyclic group (e.g., dioxolanyl, 2-methyl-1,3-dioxolane-2-yl, pyrrolidinyl, and piperidino), optionally substituted heteroaryl (e.g., 2-pyridyl, 3-pyridyl, 4-pyridyl, pyridine N-oxide-4-yl, 1-methyl-2-pyridone-4-yl, 1-pyrrolyl, 2-pyrrolyl, and 3-pyrrolyl), and the like. These substituents may be substituted at one or more possible position(s). Preferably, optionally substituted amino, halogen, nitro, alkyl, and alkyloxy are exemplified.
Examples of xe2x80x9coptionally substituted arylxe2x80x9d are phenyl, 2-aminophenyl, 3-aminophenyl, 4-aminophenyl, 2-acetylaminophenyl, 4-acetylaminophenyl, 2-benzoylaminophenyl, 4-benzoylaminophenyl, 2-methylsulfonylaminophenyl, 2-propionylaminophenyl, 2-methylaminophenyl, 4-methylaminophenyl, 2-dimethylaminophenyl, 4-dimethylaminophenyl, 2-ethylaminophenyl, 4-ethylaminophenyl, 4-diethylaminophenyl, 2- (4-methoxyphenylsulfonylamino)phenyl, 2-hydroxyphenyl, 4-hydroxyphenyl, 2-ethyloxycarbonylmethyloxyphenyl, 2-carboxymethyloxyphenyl, 2-chlorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-iodophenyl, 4-trifluoromethylphenyl, 2-methylphenyl, 4-methylphenyl, 4-methyloxyphenyl, 4-ethyloxyphenyl, 4-n-propyloxyphenyl, 4-isopropyloxyphenyl, 4-tert-butyloxycarbonylphenyl, 4-prenyloxyphenyl, 2-nitrophenyl, 4-nitrophenyl, 4-(4-methoxyphenylmethyloxy)phenyl, 4-methyloxycarbonylphenyl, 4-aminosulfonylphenyl, 4-(N, N-dimethylaminocarbonyl)phenyl, 4-carboxyphenyl, 4-biphenylyl, 4-benzoylphenyl, 4-pyrrolidinophenyl, 4-piperidinophenyl, 2-(3-amino)naphthyl, 2-amino-5-chlorophenyl, 2-amino-3-chlorophenyl, 2-amino-4-chlorophenyl, 2-amino-6-chlorophenyl, 4-amino-2-chlorophenyl, 2-amino-4-fluorophenyl, 2-amino-5-fluorophenyl, 2-amino-6-fluorophenyl, 4-amino-2-fluorophenyl, 2-amino-4,5-difluorophenyl, 2-amino-3-methylphenyl, 2-amino-4-methylphenyl, 2-amino-5-methylphenyl, 2-amino-6-methylphenyl, 4-amino-3-methylphenyl, 4-amino-3-methyloxyphenyl, 2-amino-4-nitrophenyl, 4-amino-3-hydroxyphenyl, 2-amino-4-carboxyphenyl, 2-amino-4-methyloxycarbonylphenyl, 4-amino-2-hydroxyphenyl, 4-amino-3-(4-methoxyphenylmethyloxy)phenyl, 2, 4-diaminophenyl, 3,4-diaminophenyl, 2-(N-acetyl-N-methylamino)phenyl, 2-acetylamino4-fluorophenyl, 2-acetylamino-4-chlorophenyl, 2,3-dichlorophenyl, 2,4-dichlorophenyl, 2-(3-amino)naphthyl, 4-amino-2-methylphenyl, 2-fluoro-4-nitrophenyl, 4-amino-2-methyloxyphenyl, 2-methyloxy-4-nitrophenyl, 4-fluoro-2-nitrophenyl, 4-amino-2-trifluoromethylphenyl, 4-amino-2-ethyloxyphenyl, 4-amino-2-trifluoromethyloxyphenyl, 2-chloro-4-nitrophenyl, 2-methyl-4-nitrophenyl, 4-nitro-2-trifluoromethyloxyphenyl, 4-nitro-2-trifluoromethylphenyl, 2-ethyloxy-4-nitrophenyl, and the like.
Examples of xe2x80x9coptionally substituted heteroarylxe2x80x9d are 3-pyridyl, 3-(2-amino)pyridyl, 5-(2-amino)pyridyl, 2-(3-amino)pyrazinyl, 4-(3-amino)pyrazolyl, 5-(4-amino-2-methyl)pyrimidinyl, 3-(2-amino)thienyl, 2-(3-methyl)thienyl, 2-(5-methyl)thienyl, 2-furyl, 3-furyl, 3-(2-methyl)turyl, 3-(2,5-dimethyl)furyl, 2-(5-bromo)faryl, 4-(2-nitro)furan, 3-(1-methyl-4-nitro)pyrazolyl, 5-(1-methyl-4-nitro)pyrazolyl, 3-(5-nitro)pyrazolyl, 3-(4-nitro)pyyazoyl, 2-(3-pyridyl)-thiazole-4-yl, 2-(4-pyridyl)-thiazole4-yl, 6-(1-pyrrolyl)-pyridine-3-yl, N-methyl-2-pyridone-3-yl, and the like.
Examples of xe2x80x9coptionally substituted 5-membered heteroaryl-diylxe2x80x9d are 2,5-flurandiyl, 2,5-thiophendiyl, 2,5-pyrroldiyl, 3,5-pyrazoldiyl, 2,5-(1,3,4-oxadiazole)diyl, 3,5-(1,2,4-oxadiazole)diyl, 2,5-oxazoldiyl, 3,5-isooxazoldiyl, 2,5-(1,3,4-thiadiazole)diyl, 3,5-(1,2,4-thiadiazole)diyl, 3,5-(4H-1,2,4-triazole)diyl, 3,5-(1-methylpyrazole)diyl, and the like.
Examples of xe2x80x9coptionally substituted arylalkenylxe2x80x9d are 4-aminophenylethenyl and the like.
Preferable example of R1 to R6, X, Y, and Z of the compound represented by the formula (I) are shown below as groups (a) to (s).
R1 and R2 are (a) each independently hydrogen atom, optionally substituted alky, alkenyl, or alkynyl; (b) each independently hydrogen atom, alkyl optionally substituted with halogen, alkenyl, or alkynyl; and (c) one is hydrogen atom and the other is C1 to C3 alkyl optionally substituted with halogen.
R3 and R4 are (d) each independently hydrogen atom, optionally substituted alkyl, alkenyl, or alkynyl; (e) each independently hydrogen atom, alkyl optionally substituted with halogen, alkenyl, or alkynyl; and (f) one is hydrogen atom and the other is C1 to C3 alkyl optionally substituted with halogen.
R5 is (g) hydrogen atom, alkyloxy, alkylthio, or optionally substituted alkyl; (h) hydrogen atom or alkyl; and (i) hydrogen or C1 to C2 alkyl.
R6 is (j) hydrogen atom or alkyl; and (k) hydrogen atom.
X is (l) xe2x80x94Oxe2x80x94 or xe2x80x94Sxe2x80x94; and (m) xe2x80x94Sxe2x80x94.
Y is (n) 5-membered heteroaryl-diyl; (o) 2,5-(1,3,4-oxadiazole)diyl, 3,5-(1,2,4-oxadiazole)diyl, 2,5-(1,3,4-thiadiazole)diyl, or 3,5-(1,2,4-thiadiazole)diyl; and (p) 2,5-(1,3,4-oxadiazole)diyl.
Z is (q) optionally substituted aryl or optionally substituted heteroaryl; (r) optionally substituted phenyl or optionally substituted monocyclic heteroaryl; and (s) phenyl, pyridyl, thienyl, or furyl, which are substituted with 1 to 3 substituents selected from the group consisting of optionally substituted amino, halogen, alkyl, alkyloxy, acyl, phenyl, alkyloxycarbonyl, hydroxy, nitro, or haloalkyl.
A preferred group of compounds represented by the formula (I) is shown below. [(R1, R2), (R3, R4), R5, R6, X Y]=[a, d, g, j, l, n], [a, d, g, j, l, o], [a, d, g, j, l, p], [a, d, g, j, m, n], [a, d, g, j, m, o], [a, d, g,j, m, p], [a, d, g, k, l, n], [a, d, g, k, l, o], [a, d, g, k, l, p], [a, d, g, k, m, n], [a, d, g, k, m, o], [a, d, g, km, p], [a, d, h, j, l, n], [a, d, h,j, l, o][a, d, h, j, l, p], [a, d, h, j, m, n], [a, d, h,j, m, o], [a, d, h,j, m, p], [a, d, h, k, l, n], [a, d, h, k, l, o], [a, d, h, k, l, p], [a, d, h, k, m, n], [a, d, h, k, m, o], [a, d, h, k, m, p], [a, d, i, j, l, n], [a, d, i, j, l, o], [a, d, i, j, l, p], [a, d, i, j, m, n], [a, d, i,j, m, o], [a, d, i, j, m, p], [a, d, i, k, l, n], [a, d, i, k, l, o], [a, d, i, k, l,p], [a, d, i, k, m, n], [a, d, i, k, m, o], [a, d, i, k, m, p], [a, e, g, j, l, n], [a, e, g, j, l, p], [a, e, g, j, m, n], [a, e, g, j, m, o], [a, e, g, j, m,o], [a, e, g, j, m, p], [a, e, g, k, l, n], [a, e, g, k, l, o], [a, e, g, k, m, n], [a, e, g, k, m, n], [a, e, g, k, m, o], [a, e, g, k, m, p], [a, e, h, j, l, n], [a, e, h, j, l, o], [a, e, h, j, l,p], [a, e, h,j, m, n], [a, e, h, j, m, o], [a, e, h i, m, p], [a, e, h, k, l, n], [a, e, h, k, l, o], [a, e, , k, l, p], [a, e, h, k, m, n], [a, e, h, k, m, o], [a, e, h, k, p], [a, e, i, j, l, n], [a, e, i, j, l, o], [a, e, i, j, l, p], [a, e, i, j, m, n], [a, e, i, j, m, o], [a, e, i, j, m, p], [a, e, i, k, l, n], [a, e, i, k, l, o], [a, e, i, k, 1 p], [a, e, i, k, m, n], [a, e, i, k, m, o], [a, e, i, k, m, p], [a, f, g, j, l, n], [a, f, g, j, l, o], [a, f, g,j, , p], [a, f g,j, m, n], [a, f, g, j, m, o], [a, f, g, j, m, p], [a, f, g, k, l, n], [a, f, g, k, l, o], [a, f, g, k, l, p], [a, f, g, k, m, n], [a,f, g, k, m, o], [a, f, g, k, m, p], [a, f, h, j, l, n], [a, f, h, j, o], [a, f, h, j, l, p], [a, f, h, j, m, n], [a, f, h, j, m, o], [a, f, h, j, m, p), [a, f, h, k, l, n], [a, f, h, k, l, o], [a, f, h, k, l, p], [a, f, h, k, m, n], [a, f, h, k, o], [a, f, h, k, m, p], [a, f, i, j, l, n], [a, f i, j, l, o], [a, f, i, j, l, p], [a, f, i, j, m, n], [a, f, i, j, m, o], [a, f, i, j, m, p], [a, f i, k, l, n], [a, f, i, k, l, o], [a, f, i, k, l, p], [a, f, i, k, m, n], [a, f, i, k, m, o], [a, f, i, k, n, p], [b, d, g, j, l, n], [b, d, g, j, l, o], [b, d, g, j, l, p], [b, d, g, j, m, n], [b, d, g, j, m, o], [b, d, g, j, m, p], [b, d, g, k, l, n], [b, d, g, k, l, o], [b, d, g, k, l, p], [b, d, g, k, m, n], [b, d, g, k, m o], [b, d, g, k, m, p], [b, d, h, j, l, n], [b, d, h, j, l, o], [b, d, h, j, l, p], [b, d, h, j, m, n], [b, d, h, j, m, o], [b, d, h, j, m, p], [b, d, h, k, l, n], [b, d, h, k, l, o], [b, d, h, k, l, p], [b, d, h, k, m, n], [b, d, h, k, m, o], [b, d, h, k, m, p], [b, d, i, j, l, n ], [b, d, i, j, l, o], [b, d, i, j, l, p], [b, d, i, j, l, n], [b, d, i, j, m, o], [b, d, i, j, m, p], [b, d, i, k, l, n], [b, d, i, k, l, o], [b, d, i, k, l, p], [b, d, i, k, m, n], [b, d, i, k, m, o], [b, d, i, k, m, p], [b, e, g, j, l, n], [b, e, g, j, l, o], [b, e, g, j, l, p], [b, e, g, j, m, n], [b, e, g, j, m, o], [b, e, g, j, m, p], [b, e, g, k, l, n][b, e, g, k, l, o], [b, e, g, k, l, p], [b, e, g, k, m, n], [b, e, g, k, m, o], [b, e, g, k, m, p], [b, e, h, j, l, n], [b, e, h, j, l, o], [b, e, h, j, l, p], [b, e, h, j, m, n], [b, e, h, j, m, o], [b, e, h, j, m, p], [b, e, h, k, l, n], [b, e, h, k, l, o], [b, e, h, k, l, p], [b, e, h, k, m, n], [b, e, h, k, m, o], [b, e, h, k, m, p], [b, e, i, j, l, n], [b, e, i, j, l, o], [b, e, i, j, l, p], [b, e, i, j, m, n], [b, e, i, j, m, o], [b, e, i, j, m, p], [b, e, i, k, l, n], [b, e, i, k, l, o], [b, e, i, k, l, p], [b, e, i, k, m, n], b, e, i, k, m, o], [b, e, i, k, m, p], [b, f, g, j, l, n], [b, f, g, j, l, o], [b, f, g, j, l, p], [b, f, g, m, n], [b, f, g, j, m, o], [b, f, g, j, m, p], [b, f, g, k, l, n], [b, f, g, k, l, o], [b, f, g, k, l, p], [b, f, g, k, m, n], [b, f, g, k, m, o], [b, f, g, k, m, p], [b, f, h, j, l, n], [b, f, h, j, l, o], [b, f, h, j, l, p], [b, f, h, j, m, n], [b, f, h, j, m, o], [b, f, h, j, m, p], [b, f, h, k, l, n], [b, f, h, k, l, o], [b, f, h, k, l, p], [b, f, h, k, m, n], [b, f, h, k, m, o], [b, f, h, k, m, p], [b, f, i, j, l, n], [b, f, i, j, l, o], [b, f, i, j, l, p], [b, f, i, j, m, n,], [b, f, i, j, m, o], [b, f, i, j, m, p], [b, f, i, k, l, n], [b, f, i, k, l, o], [b, f, i, k, l, p], [b, f, i, k, m, n], [b, f, i, k, m, o], [b, f, i, k, m, p], [c, d, g, j, l, n], [c, d, g, j, l, o], [c, d, g, j, l, p], [c, d, g, j, m, n], [c, d, g, j, m, o], [c, d, g, j, m, p], [c, d, g, k, l, n], [c, d, g, k, l, o], [c, d, g, k, l, p], [c, d, g, k, m, n], [c, d, g, k, m, o], [c, d, g, k, m, p], [c, d, h, j, l, n], [c, d, h, j, l, o], [c, d, h, j, l, p], [c, d, h, j, m, n], [c, d, h, j, m, o], [c, d, h, j, m, p], [c, d, h, k, l, n], [c, d, h, k, l, o], [c, d, h, k, l, p], [c, d, h, k, m, n], [c, d, h, k, m, o], [c, d, h, k, m, p], [c, d, i, j, l, n], [c, d, i, j, l, o], [c, d, i, j, l, p], [c, d, i, j, m, n], [c, d, i, j, m, o], [c, d, i, j, m, p], [c, d, i, k, l, n], [c, d, i, k, l, o], [c, d, i, k, l, p], [c, d, i, k, m, n], [c, d, i, k, m, o], [c, d, i, k, m, p], [c, e, g, j, l, n], [c, e, g, j, l, o], [c, e, g, j, l, p], [c, e, g, j, m, n], [c, e, g, j, m, o], [c, e, g, j, m, p], [c, e, g, k, l, n], [c, e, g, k, l, o], [c, e, g, k, l, p], [c, e, g, k, m, n], [c, e, g, k, m o], [c, e, g, k, m, p], [c, e, h, j, l, n], [c, e, h, j, l, o], [c, e, h, j, l, p], [c, e, h, j, m, n], [c, e, h, j, m, o], [c, e, h, j, m, p], [c, e, h, k, l, n], [c, e, h, k, l, o], [c, e, h, k, l ,p], [c, e, h, k, m, n], [c, e, h, k, m, o], [c, e, h, k, m, p], [c, e, i, j, l, n], [c, e, i, j, l, o], [c, e, i, j, l, p], [c, e, i, j, m, n], [c, e, i, j, m, o], [c, e, i, j, m, p], [c, e, i, k, l, n], [c, e, i, k, l, o], [c, e, i, k, l, p], [c, e, i, k, m, n], [c, e, i, k, m, o], [c, e, i, k, m, p], [c, f, g, j, l, n], [c, f, g, j, l, o], [c, f, g, j, l, p], [c, f, g, j, m, n], [c, f, g, j, m, o], [c, f, g, j, m, p], [c, f, g, k, l, n], [c, f, g, k, l, o], [c, f, g, k, l, p], [c, f, g, k, m n], [c, f, g, k, m, o], [c, f, g, k, m, p], [c, f, h, j, l, n], [c, f, h, j, l, o], [c, f, h, j, l, p], [c, f, h, j, m, n], [c, f, h, j, m, o], [c, f, h, j, m, p], [c, f, h, k, l, n], [c, f, h, k, l, o], [c, f, h, k, l, p], [c, f, h, k, m, n], [c, f, h, k, m, o], [c, f, h, k, m, p], [c, f, i, j, l, n], [c, f, i, j, l, o], [c, f, i, j, l, p], [c, f, i, j, m, n], [c, f, i, j, m, o], [c, f, i, j, m, p], [c, f, i, k, l, n], [c, f, i, k, l, o], [c, f, i, k, l, p], [c, f, i, k, m, n], [c, f, i, k, m, o], [c, f, i, k, m, p]
Preferred embodiments of this invention are compounds wherein Z is any one of (q) to (s) and [(R1, R2), (R3, R4), R5, R6, X, Y] is any one of the above combinations.
In this specification, the compound represented by the formula (I) wherein R1 is hydrogen atom may be represented as an isomer of the following formula (V): 
wherein R2, R3, R4, R5, R6, X, Y, and Z are as defined above and R1 is hydrogen atom.
The compounds represented by the formula (II), (III), and (IV) may be each isomer as well.
The compound represented by the formula (XXV): 
wherein one of R15 and R16 is xe2x80x94NR1R2 wherein R1 and R2 are each independently hydrogen atom, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, an optionally substituted non-aromatic heterocyclic group, or acyl, or R1 and R2 together with the adjacent nitrogen atom may form 3- to 6-membered ring, and the other is alkylthio;
or both of R15 and R16 are alkylthio;
R5 and R6 are each independently hydrogen atom, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alknyl, optionally substituted alkyloxy, alkylthio, optionally substituted alkyloxycarbonyl, optionally substituted aryl, optionally substituted heteroaryl, halogen, hydroxy, mercapto, optionally substituted amino, carboxy, cyano, or nitro;
X is xe2x80x94N(R7)xe2x80x94, xe2x80x94NHxe2x80x94NHxe2x80x94, xe2x80x94Oxe2x80x94, or xe2x80x94Sxe2x80x94 wherein R7 is hydrogen atom or optionally substituted alkyl;
Y is optionally substituted 5-membered non-aromatic heterocycle-diyl or optionally substituted 5-membered heteroaryl-diyl; and
Z is optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted alkenyl;
the prodrugs thereof, or their pharmaceutically acceptable salts, or their solvates are also useful as a pharmaceutical composition, an anti tumor agent, a cytostatic agent, and an inhibitor against a signal derived from Ras oncogene products.
The compound of the present invention represented by the formula (I) can be synthesized by the well-known method described in the literature of chemistry. A summary of the useful method for synthesis of the compound of the present invention is shown below.
(Synthetic method) 
wherein R1, R2, R3, R4, R5, R6, X, Y, and Z are as defined above; R13 is hydrogen atom or a protective group of a hydroxy group.
The compound represented by the formula (I) can be synthesized by reacting Zxe2x80x94Yxe2x80x94XH (VI) with the guanidinopyrimidine derivatives (VII). The guanidinopyrimidine derivatives (VII) in a solvent such as water, acetic acid, pyridine, and the like is treated with a hydrohalogenic acid such as hydrochloric acid and hydrobromic acid to give hydrogen halide salts of 5-halogenomethylpyrimidine. When R13 is hydrogen atom, a halogenation agent such as thionyl halide and phosphorous halide can be used. The obtained salt and Zxe2x80x94Yxe2x80x94XH (VI) in a solvent such as water, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, tetrahydrofuran are reacted with an appropriate base, for example an inorganic base such as sodium hydroxide, potassium butoxide, sodium hydride, potassium hydride, and potassium carbonate or an organic base such as triethylamine, pyridine, and diisopropylethylamine, at xe2x88x9220xc2x0 C. to 100xc2x0 C., preferably 0xc2x0 C. to 30xc2x0 C. for 1 min to 24 h, preferably 10 min to 12 h to give the aimed compound (I).
Compound (VI) and compound (VII) can be synthesized by the methods A to I and the methods J to N as shown below.
In the methods A to I, Z represents optionally substituted aryl or optionally substituted heteroaryl. The starting material of each method is commercially available or can be synthesized by well-know method from the compound which is commercially available.
Method A: Synthetic method of the compound wherein Y is an oxadiazole ring and X is xe2x80x94Sxe2x80x94. 
Compound (VIII) in a solvent such as ethanol and benzene is reacted with carbon disulfide and a base such as triethylamnine, sodium hydroxide, potassium carbonate at 0xc2x0 C. to 100xc2x0 C., preferably 60xc2x0 C. to 100xc2x0 C. for 10 min to 24 h, preferably 2 h to 12 h to give compound (VI-1).
Method B: Synthetic method of the compound wherein Y is an oxadiazole ring and X is xe2x80x94Oxe2x80x94. 
To a solution of compound (VIII) in a solvent such as tetrahydrofuran and toluene is added carbonyldiimidazole and the mixture is reacted at 0xc2x0 C. to 120xc2x0 C., preferably 60xc2x0 C. to 120xc2x0 C. for 10 min to 24 h, preferably 2 h to 12 h to give compound (VI-2).
Method C: Synthetic method of the compound wherein Y is an oxadiazole ring and X is xe2x80x94N(R7)xe2x80x94. 
wherein R7 is as defined above.
To a solution of compound (IX) in a solvent such as ethanol and tetrahydroftiran is added mercury oxide and the mixture is reacted at 0xc2x0 C. to 120xc2x0 C., preferably 30xc2x0 C. to 80xc2x0 C. for 0.5 h to 24 h, preferably 1 h to 24 h to give compound (VI-3).
Method D: Synthetic method of the compound wherein Y is a thiadiazole ring and X is xe2x80x94Sxe2x80x94. 
To a solution of compound (VIII) in a solvent such as ethanol and tetrahydrofuran are added carbon disulfide and a base such as triethylamine and sodium hydroxide and the mixture is reacted at 0xc2x0 C. to 100xc2x0 C., preferably 20xc2x0 C. to 60xc2x0 C. for 0.5 h to 24 h, 1 h to 12 h. After the solvent is removed, the residue is reacted with conc. sulfuric acid at xe2x88x9220xc2x0 C. to 40xc2x0 C., preferably 0xc2x0 C. to 20xc2x0 C. for 1 min to 12 h, preferably 10 min to 1 h to give compound (VI-4).
Method E: Synthetic method of the compound wherein Y is a furan ring and X is xe2x80x94Sxe2x80x94. 
(Step 1)
Halogenated furan such as 2-bromofuran is reacted with compound (X) in a solvent such as dimethylformamide, toluene, xylene, benzene, tetrahydrofliran, and ethanol in the presence of palladium catalyst such as Pd(Ph3P)4 and a base such as potassium carbonate, calcium carbonate, triethylamine, and sodium methoxide to give the aimed compound (XI) (Suzuki reaction). The reaction temperature is room temperature to 100xc2x0 C., preferably room temperature to 80xc2x0 C. and the reaction time is 5 to 50 h, preferably 15 to 30 h.
(Step 2)
To a solution of compound (XI) in a solvent such as tetrahydrofuran, diethyl ether, and toluene is added a base such as n-butyllithium and sec-butyllithium and the mixture is stirred at xe2x88x92100xc2x0 C. to 50xc2x0 C., preferably xe2x88x9280xc2x0 C. to 0xc2x0 C. for 1 min to 24 h, preferably 10 min to 60 min. To the mixture is added sulfur and the resulting mixture is reacted at xe2x88x92100xc2x0 C. to 50xc2x0 C., preferably xe2x88x9280xc2x0 C. to 0xc2x0 C. for 1 h to 24 h, preferably 1 h to 12 h to give the a compound (VI-5).
Method F: Synthetic method of the compound wherein Y is a thiophene ring and X is xe2x80x94Sxe2x80x94. 
wherein Hal is halogen.
The steps 1 and 2 can be carried out in a manner similar to those described in step 1 and 2 of Method E.
Method G: Synthetic method of the compound wherein Y is an oxazole ring and X is xe2x80x94Sxe2x80x94. 
To a solution of compound (XIII) in a solvent such as dichloromethane, toluene, and diethyl ether is added thiophosgene in the presence of a base such as triethylamine and sodium hydroxide and the mixture is reacted at xe2x88x9220xc2x0 C. to 100xc2x0 C., preferably 0xc2x0 C. to 40xc2x0 C. for 1 h to 48 h, preferably 1 h to 24 h to give compound (VI-7).
Method H: Synthetic method of the compound wherein Y is an oxazole ring and X is xe2x80x94Oxe2x80x94 or xe2x80x94Sxe2x80x94. 
(Step 1)
Compound (XIV) in a solvent such as dichloromethane and acetonitrile is reacted with a condensing agent such as dicyclohexylcarbodiimide at xe2x88x9220xc2x0 C. to 50xc2x0 C., preferably 0xc2x0 C. to 20xc2x0 C. for 5 min to 24 h, preferably 10 min to 2 h to give compound (VI-8).
(Step 2)
To a solution of compound (VI-8) in a solvent such as toluene and dioxane is added Lawesson""s reagent and the mixture is reacted at 60xc2x0 C. to 150xc2x0 C., preferably 80xc2x0 C. to 120xc2x0 C. for 1 h to 24 h, preferably 2 to 12 h to give compound (VI-9).
Method I: Synthetic method of the compound wherein Y is an isoxazole ring and X is xe2x80x94Oxe2x80x94 or xe2x80x94Sxe2x80x94. 
wherein R14 is C1 to C3 alkyl.
(Step 1)
Compound (XV) in a solvent such as methanol and tetrahydrofuran is reacted with hydroxylamine at 20xc2x0 C. to 100xc2x0 C., preferably 50xc2x0 C. to 80xc2x0 C. for 1 h to 24 h, preferably 2 h to 12 h to give compound (VI-10).
(Step 2)
Compound (VI-11) can be obtained in a manner similar to that described in step 2 of Method H.
The compounds which are not concretely shown in the above methods can be synthesized by a combination of some of the above methods A to I and well-know method.
In the methods J to N, R1, R2, R3, R4, R5, R6, and R13 are as defined above. The starting material of each method is commercially available or can be synthesized by well-know method from the compound which is commercially available.
Methods J and K are process for construction of a pyrimidine ring and can be carried out in accordance with well-known method (see Journal of Chemical Society, 1937, p-364, ibid., 1943, p-388 and J. Pharm. Soc. Japan 1954, p-742).
Methods L to N are processes that a guanidino group is introduced to the pyrimidine derivative obtained in the Method J and Method K and can be carried out in accordance with well-known method (see Journal of Chemical Society, 1948, p-58, ibid., 1946, p-1063 and Synthesis, 1988, p-460).
Method J: Synthesis of a pyrimidine ring 
(Step 1)
Compound (XVI) in a solvent such as ethanol, tetrahydrofuran, and dimethylformamide is reacted with R5xe2x80x94C(xe2x95x90S)xe2x80x94NH2 in the presence of a base such as sodium ethylate and sodium hydroxide at 0xc2x0 C. to 150xc2x0 C., preferably 60xc2x0 C. to 100xc2x0 C. for 0.5 h to 48 h, preferably 1 h to 12 h to give compound (XVII).
(Step 2)
Compound (XVII) in a solvent such as ether and tetrahydrofuran or a mixed in solvent such as ether-tetrahydrofuran is reacted with a reducing agent such as lithium aluminum hydride and lithium borohydride at xe2x88x9280xc2x0 C. to 100xc2x0 C., preferably xe2x88x9220xc2x0 C. to 40xc2x0 C. for 0.5 h to 24 h, preferably 1 h to 12 h to give an alcohol derivative. The obtained alcohol derivative is protected by the method described in Protective Groups in Organic Synthesis, Theodora W Green (John Wiley and Sons) and the like to give compound (XVIII). Methyl, ethyl, trimethylsilyl, tert-butyldimetylsilyl, and the like are exemplified as R13.
Method K: Synthesis of a pyrimidine ring 
(Step 1)
Compound (XIX) in a solvent such as ethanol, tetrahydrofuran, and dimethylformamide is reacted with R5xe2x80x94C(xe2x95x90NH)xe2x80x94NH2 or its salt in the presence of a base such as sodium ethylate and sodium hydroxide at 0xc2x0 C. to 150xc2x0 C., preferably 60xc2x0 C. to 100xc2x0 C. for 0.5 h to 48 h, preferably 1 h to 12 h to give compound (XX) or its salt.
(Step 2)
Compound (XX) or its salt in a solvent such as toluene and dichloroethane or without a solvent is reacted with a halogenation agent such as thionyl chloride and phosphorus oxychloride at 0xc2x0 C. to 150xc2x0 C., preferably 60xc2x0 C. to 120xc2x0 C. for 0.5 h to 12 h, preferably 1 h to 5 h to give a halogenated derivative. The obtained halogenated derivative in a solvent such as ethanol and tetrahydrofuran is reacted with R1NH2 at xe2x88x9280xc2x0 C. to 100xc2x0 C., preferably xe2x88x9220xc2x0 C. to 30xc2x0 C. for 0.5 h to 48 h, preferably 1 h to 12 h to give compound (XX).
(Step 3)
This step can be carried out in a manner similar to that described in step 2 of Method J.
Method L: Introduction of a guanidino group 
(Step 1)
Compound (XVIII) in a solvent such as dimethylformamide, pyridine, and tetrahydrofuran is reacted with R3-NCS or R3R4NCS-Hal wherein Hal is halogen in the presence or absence of a base such as sodium hydride at xe2x88x9220xc2x0 C. to 120xc2x0 C., preferably 0xc2x0 C. to 120xc2x0 C. for 0.5 h to 48 h, preferably 1 h to 24 h to give compound (XXII).
(Step 2)
To a solution of compound (XXII) in a solvent such as methanol and tetrahydrofiran are added a heavy metal salt or heavy metal oxide such as HgO and R1R2NH and the mixture is reacted at xe2x88x9220xc2x0 C. to 100xc2x0 C., preferably 0xc2x0 C. to 50xc2x0 C. for 0.5 h to 48 h, preferably 1 h to 12 h to give compound (VII).
Method M: Introduction of a guanidino group 
(Step 1)
Compound (XVIII) in a solvent such as dimethylformamide and tetrahydrofuran is reacted with a base such as sodium hydride and potassium butoxide at 0xc2x0 C. to 100xc2x0 C., preferably 20xc2x0 C. to 60xc2x0 C. for 0.5 h to 48 h, preferably 1 h to 12 h. To the mixture are added carbon disulfide and then methyl iodide and the resulting mixture is reacted at 0xc2x0 C. to 100xc2x0 C., preferably 20xc2x0 C. to 60xc2x0 C. for 0.5 h to 48 h, preferably 1 h to 12 h to give compound (XXII).
(Step 2)
Compound (XXIII) in a solvent such as methanol and dimethylformamide is reacted with R3R4NH at 0xc2x0 C. to 150xc2x0 C., preferably 0xc2x0 C. to 100xc2x0 C. for 0.5 h to 48 h, preferably 1 h to 12 h to give compound (XXIV).
(Step 3)
Compound (XXIV) in a solvent such as methanol and dimethylformamide is reacted with R1R2NH at 20xc2x0 C. to 150xc2x0 C., preferably 40xc2x0 C. to 80xc2x0 C. for 0.5 h to 48 h, preferably 4 h to 24 h to give compound (VII).
Method N: Introduction of a guanidino group (R1xe2x95x90H) 
(Step 1)
This step can be carried out in a manner similar to that described in step 1 of Method L.
(Step 2)
This step can be carried out in a manner similar to that described in step 2 of Method L.
When a compound contains a functional group(s) possibly interfering the reaction such as hydroxy, mercapto, and amino in the each step of Method A to Method N, it can previously be protected and deprotected at an appropriate stage in accordance with the literature such as Protective Groups in Organic Synthesis, Theodora W. Green (John Wiley and Sons).
In the specification, the term xe2x80x9csolvatexe2x80x9d includes, for example, solvates with organic solvents, hydrates, and the like.
The term xe2x80x9cthe compounds of the present inventionxe2x80x9d herein used includes pharmaceutically acceptable salts and hydrates of the compounds. For example, salts with alkali metals (e.g., lithium, sodium, and potassium), alkaline earth metals (e.g., magnesium and calcium), ammonium, organic bases, amino acids, mineral acids (e.g., hydrochloric acid, hydrobromic acid, phosphoric acid, and sulfuric acid), or organic acids (e.g., acetic acid, citric acid, maleic acid, fumaric acid, benzenesulfonic acid, and p-toluenesulfonic acid) and hydrates of them are exemplified. These salts and hydrates can be formed by usual methods. The hydrates may coordinate with an arbitrary number of water molecules.
Prodrug is a derivative of the compound of the present invention having a group which can be decomposed chemically or metabolically, and such prodrug is converted to a pharmaceutically active compound of the present invention by means of solvolysis or by placing the compound in vivo under a physiological condition. The selection method and the process method of an appropriate prodrug derivative are described in the literature such as Design of Prodrugs, Elsevier, Amsterdam 1985. When the compounds of the present invention have a carboxyl group, an ester derivative prepared by reacting a basal acid compound with a suitable alcohol or an amide prepared by reacting a basal acid compound with a suitable amine are exemplified as prodrugs. Particularly preferred esters as prodrugs are methyl ester, ethyl ester, n-propyl ester, isopropyl ester, n-butyl ester, isobutyl ester, tert-butyl ester, morpholinoethyl ester, N, N-diethylglycolamido ester, and the like. When the compounds of the present invention have a hydroxy group, an acyloxy derivative prepared by reacting with a suitable acyl halide or a suitable acid anhydride are exemplified as prodrugs. Particularly preferred acyloxy derivatives as prodrugs are xe2x80x94OCOC2H5, xe2x80x94OCOtxe2x80x94Bu, xe2x80x94OCOC15H31, xe2x80x94OCO(mxe2x80x94COONaxe2x80x94Ph), xe2x80x94OCOCH2CH2COONa, xe2x80x94OCOCH(NH2)CH3, and xe2x80x94OCOCH2N(CH3)2, and the like. When the compounds of the present invention have an amino group, an amide derivative prepared by reacting with a suitable acid halide or a suitable acid anhydride are exemplified as prodrugs. Particularly preferred amide derivatives as prodrugs are xe2x80x94NHCO(CH2)20CH3 and xe2x80x94NHCOCH(NH2)CH3, and the like.
The compound of the present invention is not restricted to any particular isomers but includes all possible isomers and racemic modifications.
The compounds of the present invention have an inhibitory activity against a signal derived from Ras oncogene products as shown in the experimental examples below.
Consequently, the compounds of the present invention can be used as a therapeutic agent for cancer.
When the compound of this invention is administered to a patient for the treatment or prevention of the above diseases, it can be administered by oral administration such as powder, granules, tablets, capsules, pilulae, and liquid medicine, or by parenteral administration such as injections, suppository, percutaneous formulations, insufflation, or the like. An effective amount of the compound of tis invention is formulated by being mixed with appropriate medicinal admixture such as excipient, binder, penetrant, disintegrators, lubricant, and the like, if necessary. When parenteral injection is prepared, the compound of this invention and an appropriate carrier are sterilized to prepare it.
An appropriate dosage varies with the conditions of the patients, an administration route, their age, and their body weight. In the case of oral administration to an adult, the dosage can generally be between 0.01-100 mg/kg/day, preferably 0.1-20 mg/kg/day.
The following examples are provided to further illustrate the present invention and are not to be construed as limiting the scope thereof.
In the examples, the following abbreviations are used.
Me: methyl
Et : ethyl
Pr: n-propyl
i-Pr: isopropyl
Bu : n-butyl
i-Bu: isobutyl
tBu: tert-butyl
Ac: acetyl
Ph: phenyl
MPM: p-methoxyphenylmethyl
DMF: dimethylformamide
THF: tetrahydrofuran
DMSO: dimethylsulfoxide
TsOH: p-toluene sulfonic acid
TBS : tert-butyldimethylsilyl
In 1H-NMR, the value of xcex4 is represented by ppm, s is singlet, d is doublet, t is triplet, q is quartet, quit is quintet, sext is sextet, and br is broad. The value of J is represented by Hz.